A long standing goal of immunogenetics has been to understand the genetic basis of antibody diversity and responsiveness, to understand both the mechanisms through which the apparently limitless variety of antibody sequences are created and the reasons these mechanisms are used. This knowledge may enable the manipulation of the antibody response-positively, to enhance vaccine response and efficacy, negatively, to dampen and suppress autoantibody or anti-organ graft responses. Among other possibilities a thorough understanding of the structural range of combining sites encoded in the genetic repertoire should lead to a rational and accelerated strategy for vaccine development. Our aim is to complete the determination of the structure, and the complete sequence, of the immunoglobulin heavy chain (Igh) locus in two strains of mice; we will complete the assembly of Bacterial Artificial Chromosome (BAC) contigs from 129 and C57BL/6; we will identify every variable region (Vh) gene with their 5' and 3' regulatory elements. Comparison of the two mouse haplotypes and the recently sequenced human IGH locus will identify shared combining site structures that are likely to be important to the defense of both species. Comparison will also reveal conserved noncoding sequence elements; these are likely to be control elements used in the regulation of this complex locus, and we will investigate their possible roles in regulating the activation, expression, and replication of Igh.